Wiskott–Aldrich Syndrome 

Overview

Wiskott–Aldrich syndrome is a rare X-linked recessive primary immunodeficiency caused by mutations in the WAS gene, leading to defective actin cytoskeleton regulation in hematopoietic cells. It presents with the triad of eczema, recurrent infections, and thrombocytopenia with small platelets. Patients are prone to autoimmunity and malignancy. Incidence is ~1 in 100,000 live male births. Without curative therapy (HSCT), prognosis is poor.

Anatomy & Physiology 

• Normal WAS protein (WASP): Cytoskeletal regulator in hematopoietic cells, essential for immune synapse formation, migration, phagocytosis, and signal transduction.
• In WAS: Defective WASP → impaired T-cell receptor signalling, defective actin remodelling, poor immune synapse → impaired T-cell and B-cell interactions → defective adaptive immunity.
• Small, dysfunctional platelets due to abnormal megakaryocyte development.

Aetiology and Risk Factors

Aetiology

• Genetics: Mutations in WAS gene (Xp11.23), encoding WASP.
• Inheritance: X-linked recessive (males affected, carrier females usually asymptomatic).
  

Risk Factors

• Family history of affected males.
• Maternal carrier status.
  

Pathophysiology 

1. WAS gene mutation → defective WASP.
   
2. Impaired actin cytoskeleton → defective immune synapse formation.
   
3. T-cell and B-cell dysfunction → impaired antibody responses, poor memory cell formation.
   
4. Small, dysfunctional platelets → thrombocytopenia and bleeding.
   
5. Immune dysregulation → increased risk of autoimmunity and malignancy.

Clinical Manifestations

• Classic Triad:
  
  • Eczema (often severe, early onset).
  • Recurrent infections (sinopulmonary, viral, fungal).
  • Thrombocytopenia with small platelets → petechiae, bruising, epistaxis, GI bleeding.
    
• Other features:
  
  • Autoimmunity (hemolytic anaemia, vasculitis, arthritis).
  • Malignancy (lymphoma, leukemia).
• Failure to thrive in severe cases.

Diagnosis

• CBC: Thrombocytopenia with small platelets (low mean platelet volume, MPV).
• Immunology:
  
  • Low IgM.
  • Normal/↑ IgA and IgE.
  • Variable IgG.
    
• Flow cytometry: Absent/reduced WASP expression in lymphocytes.
• Genetic testing: Confirms WAS gene mutation.
• Family history: X-linked inheritance pattern.
  

Differential Diagnosis

Condition	Differentiating Feature
Atopic dermatitis	Eczema but no thrombocytopenia or recurrent severe infections
ITP (immune thrombocytopenia)	Thrombocytopenia but normal platelet size and no immunodeficiency
SCID	Severe infections but no thrombocytopenia or eczema
Hyper-IgE syndrome	Eczema + infections but normal/large platelets

Treatment

• Curative: Haematopoietic stem cell transplantation (HSCT).
• Emerging: Gene therapy (trials ongoing).
• Supportive:
  
  • IVIG for antibody deficiency.
  • Prophylactic antibiotics.
  • Platelet transfusions if severe bleeding.
  • Eczema management (topical therapy, infection control).
• Avoid aspirin/NSAIDs.

Complications & Prognosis

• Life-threatening bleeding (GI, intracranial).
• Severe recurrent infections.
• Autoimmune disease (20–40%).
• Lymphoma/leukaemia risk markedly increased.
• Prognosis: Poor without HSCT (death in childhood); greatly improved survival with early HSCT.